The use of immunoglobulins as therapeutic treatment for a variety of diseases and disorders is rapidly increasing because they have shown to be safe and efficacious therapeutic agents. Approved therapeutic monoclonal antibodies for human use include Trastuzumab (antigen: 180 kD, HER2/neu), Edrecolomab (antigen: 40-50 kD, Ep-CAM), Anti-human milk fat globules (HMFG1) (antigen>200 kD, HMW Mucin), Cetuximab (antigens: 150 kD and 170 kD, EGF receptor), Alemtuzumab (antigen: 21-28 kD, CD52), and Rituximab (antigen: 35 kD, CD20). The extracellular domains of membrane-bound receptors in the immunoglobulin superfamily may be fused to antibody constant domains, or fragments thereof, to form soluble receptors having antibody-like structure and function. Approved therapeutic proteins containing constant domains derived from antibodies for human use include etanercept, a fusion of the TNF receptor and an Fc domain from human IgG1. Additional therapeutic proteins are in various phases of clinical development for humans for a variety of diseases with the majority targeting various forms of cancer and inflammatory-related diseases.
Antibodies target an antigen through its binding of a specific epitope on an antigen by the interaction with the variable region of the antibody molecule. At the same time, the constant region of the antibody may additionally recruit other cells or molecules for example to destroy the cell or protein to which the antibody is bound or trigger further immune reactions. Certain regions of the immunoglobulin constant domain may elicit antibody-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), phagocytosis, immediate hypersensitivity, regulation of the Ig synthesis, and antigen presenting cells. The ability of the immunoglobulin constant domain regions to bind to certain receptors on certain types of cells is a feature that can be exploited to alter the effects of a polypeptide including these constant domain regions and/or fragment thereof. In some cases, for example, it might be desirable to lyse the cell to which the antibody binds; in other cases, not. This function can be controlled by manipulation of the constant domain.
Whereas the structural features and biological functions of the constant domain regions have been intensively studied in several mammalian species such as humans and mice, they have been less studied in companion animals such as canine, feline, and equine mammals. A recombinant polypeptide containing a modified Ig constant domain region or fragment thereof may enhance the therapeutic efficacy of a recombinant monoclonal antibody or Ig-fusion protein for companion animals such as dogs, cats and horses.